In drug delivery systems, chemical modification of biofunctional molecules or drug carriers with a hydrophilic polymer having low antigenicity is an effective technique for increasing water solubility and bioavailability of these drugs and the like and for prolonging circulation time in blood. On the other hand, it is known that the formation of a hydrated layer by the hydrophilic polymer decreases interaction with cell membranes and inhibits in vivo/intracellular kinetics such as uptake into cells and endosome escape after the drugs and the like bound to the hydrophilic polymer are transported to the tissue or site to be a target. For such problems, an approach to overcome the problems by detaching the hydrophilic polymer chain from the drugs and the like at a suitable timing has been performed. Most of the strategies utilize an environmental change at each portion of the living body, such as reductive environment or the presence or absence of a specific enzyme, as a trigger of the detachment of the hydrophilic polymer chain. One of them is a technique of utilizing a change in pH.
The periphery of a tumor tissue in the living body is known to be an acidic environment as compared to normal tissues and the pH of endosomal interior after the drugs and the like are introduced into cells via an endocytosis pathway also gradually decreases. Accordingly, for the purpose of selectively detaching the hydrophilic polymer under the acidic environment, there have been reported a large number of synthetic examples of hydrophilic polymer derivatives having an acid hydrolyzable acetal linker introduced into the structure. However, there are no examples in which the hydrolyzability of the acetal linker can be controlled and not a few examples involve a problem in the method of introducing the acetal linker.
For example, Patent Document 1 discloses a branched polyethylene glycol derivative, in which two chains of polyethylene glycol that is a hydrophilic polymer having low antigenicity are bound via an acetal group that is derived from various aldehydes or ketones, and a synthetic method thereof but does not describe any evaluation data of hydrolyzability. Also, the synthetic method described therein is a method for obtaining a polyethylene glycol derivative having an acetal linker by reacting an excess amount of polyethylene glycol for various aldehydes or ketones and hence much unreacted polyethylene glycol remains after the reaction. In the case where activation of the polymer end is performed using the mixture as a raw material, an impurity in which the end of the unreacted polyethylene glycol has been also activated is formed as a by-product. When the activated polyethylene glycol containing such an impurity is used for drug modification, a drug modified with the polyethylene glycol containing no acetal linker is formed as a result, so that a large influence is exerted on the in vivo kinetics and physical properties of the drug. Therefore, it is necessary to remove the polyethylene glycol impurity before the reaction with the drug but, in the case of the production in an industrial scale, there is a possibility that the separation and removal of the polymer impurity becomes a severe evil in technical and cost aspects.
As another method for obtaining an acetal compound, there is a method of reacting an alcohol with a vinyl ether under acidic conditions. For example, in Non-Patent Document 1, polyethylene glycol derivatives having various functional groups bound via ethylidene acetal linkers have been synthesized by reacting vinyl ethers having various functional groups with polyethylene glycol. However, also in this document, evaluation data of hydrolyzability are not shown.
In the synthetic method described in Non-Patent Document 1, since the vinyl ether that is a low-molecular compound is used in an excess amount to polyethylene glycol, so much amount of unreacted polyethylene glycol does not remain. However, the acetal group to be introduced by the synthetic method contains an ethylidene acetal structure, the type of the acetal group that can be introduced is limited. In the case of introducing a benzylidene acetal group, the type is necessarily a ketal structure. Since the ketal structure is sensitive to an acid, a dimer impurity in which two chains of polyethylene glycol are bound via a ketal group is much formed as a by-product by a ketal exchange reaction in the synthetic method. Accordingly, the synthetic method described in Non-Patent Document 1 is difficult to apply to the synthesis of a polyethylene glycol derivative having a benzylidene acetal linker.
On the other hand, in Non-Patent Document 2, several types of polyethylene glycol derivatives in which a low-molecular model drug is bound via an aliphatic or benzylidene acetal linker are synthesized by synthesizing a unit having an acetal group, which has been formed with utilizing the hydroxyl group of the low-molecular model drug, and condensing the unit with a separately synthesized activated polyethylene glycol derivative. In this case, although it is shown that a difference in the structure around the acetal group affects the hydrolysis rate, i.e., the detaching rate of the polyethylene glycol chain, the correlation between the rate and the structure around the acetal group has not been clarified and hence it can not be said that the hydrolyzability can be controlled. Also, since the method is a method of forming an acetal group with utilizing the hydroxyl group of the low-molecular model drug, it is difficult to use the method in the chemical modification of proteins, drug carriers, and the like other than low-molecular drugs.
As mentioned above, although there are many examples of hydrophilic polymer derivatives each having an acetal linker introduced into the structure for the purpose of detaching the hydrophilic polymer chain under an acidic environment in the living body, there is no example with regard to the hydrophilic polymer derivative in which the hydrolysis rate of the acetal linker, i.e., the detaching rate of the hydrophilic polymer chain is accurately controlled in an optional pH.